Oxypurinol as an inhibitor of xanthine oxidase-catalyzed production of superoxide radical.

Abstract

A recent study of the mechanism by which oxypurinol inhibits uric acid generation [T. Spector, W. W. Hall and T. A. Krenitsky, Biochem. Pharmac. 35, 3109(1986)] showed that xanthine is ineffective in impeding the binding of oxypurinol to reduced xanthine oxidase. This study prompted the present hypothesis that, at elevated concentrations of substrates, oxypurinol would be superior to allopurinol as an inhibitor of the xanthine oxidase-catalyzed production of superoxide radical. It was found that the potency of allopurinol was attenuated by elevated concentrations of xanthine and hypoxanthine, whereas the potency of oxypurinol was relatively unaffected. Oxypurinol produced immediate inhibition of superoxide radical production as well as progressive inhibition with time. In contrast, allopurinol, which is also a substrate for xanthine oxidase, produced very little immediate inhibition and caused progressive inhibition only after conversion to oxypurinol. The theoretical advantages of treating ischemic tissues with oxypurinol are discussed.